The Role And Mechanism Of Atorvastatin To Enhance VE-PTP Expression And Endothelial Adherent Junction

Blood continuous circulation in the blood vessels is necessary to maintain the health and life of human being.The integrity of vascular wall and maintenance of vascular hemostasis are the foundation to guarantee normal blood circulation.A variety of in vivo and in vitro pathological factors such as hyperlipidemia,hypertension,inflammation,smoking,and air pollution,can reduce the adherens junction of endothelial cells(ECs),interfere or damage the integrity and stability of blood vessels,resulting in a series of pathological changes such as vascular fragility and leakage,leading to cardiovascular and cerebrovascular diseases.VE-cadherin plays pivotal roles in EC adherens junction and vascular homeostasis,and is easily phosphorylated under pathological conditions.The phosphorylated VE-cadherin loses stability on the surface of cell membrane and is engulfed or released,causing the reduction of the protein and disruption of the adherens junction between ECs.Therefore,prevention of the VE-cadherin phosphorylation is the key point in maintaining the adherens junction between ECs and vascular hemostasis.VE-PTP is an important protein to prevent phosphorylation of VE-cadherin;however,there is no report worldwide on a drug which is able to promote VE-PTP expression,de-phosphorylate VE-cadherin,and protect EC adherens junction.Therefore,how to increase the expression of VE-PTP to protect the adherens junction between ECs and vascular hemostasis is an urgent scientific problem to be solved.In this study,we screened several small molecular compounds and found that Atorvastatin is able to promote VE-PTP expression in ECs,maintain the VE-cadherin distribution on the cell membrane surface,enhance the EC adhesion junction,and decrease the VE-cadherin phosphorylation at the position of Y731 caused by cigarette smoke extraction(CSE)and permeability between ECs.Mechanistic studies revealed that Atorvastatin was able to promote VE-PTP promoter activity.We identified the promoter region of VE-PTP activated by Atorvastatin via the series deletion approach,and found that Atorvastatin promoted VE-PTP gene transcription by enhancing the expression of transcription factor SP1 which bound to VE-PTP promoter in nuclear.For the first time,we discovered the ability of Atorvastatin to promote VE-PTP expression by escalating the expression of transcription factor SP1 which bound to VE-PTP promoter,resulting in decrease in the VE-cadherin phosphorylation at Y731 caused by CSE and permeability between ECs.This study revealed a novel function of Atorvastatin,which has important significance to maintain the vascular stability under pathological conditions.